Abstract

Several recent reports suggest that inflammatory signals play a decisive role in the self-renewal, migration and differentiation of multipotent neural stem cells (NSCs). NSCs are believed to be able to ameliorate the symptoms of several brain pathologies through proliferation, migration into the area of the lesion and either differentiation into the appropriate cell type or secretion of anti-inflammatory cytokines. Although NSCs have beneficial roles, current evidence indicates that brain tumours, such as astrogliomas or ependymomas are also caused by tumour-initiating cells with stem-like properties. However, little is known about the cellular and molecular processes potentially generating tumours from NSCs. Most pro-inflammatory conditions are considered to activate the transcription factor NF-kappaB in various cell types. Strong inductive effects of NF-kappaB on proliferation and migration of NSCs have been described. Moreover, NF-kappaB is constitutively active in most tumour cells described so far. Chronic inflammation is also known to initiate cancer. Thus, NF-kappaB might provide a novel mechanistic link between chronic inflammation, stem cells and cancer. This review discusses the apparently ambivalent role of NF-kappaB: physiological maintenance and repair of the brain via NSCs, and a potential role in tumour initiation. Furthermore, it reveals a possible mechanism of brain tumour formation based on inflammation and NF-kappaB activity in NSCs.

Neural stem cells (NSC) division in physiological situation and in acute inflammation. Physiologically, NSCs proliferate slowly and asymmetrically generating more committed precursors or differentiated cells. In an inflammatory environment, NSCs might start to proliferate rapidly and symmetrically in response to pro-inflammatory cytokines such as TNF-α. The pro-inflammatory stimuli activate the transcription factor NF-κB. After acute inflammation is attenuated, NF-κB becomes deactivated and NSCs switch back to the asymmetrical mode of division.

Model for the correlation between chronic inflammation, symmetric division of NSCs and cancer. In chronic inflammation, NSCs are permanently exposed to proliferation-inducing stimuli such as TNF-α. The ensuing rapid proliferation entails a much higher risk of mutation than slow cell division. Initial mutations could easily be propagated as a result of the fast symmetric division. Secondary mutations then may lead to constitutive NF-κB activity, aneuploidy and finally to cancer.